Position/Role: GSAT Ph.D. candidate
Field of Research: Bioinformatics, epigenetics, next-generation sequencing data analysis
Thesis: Somatic mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) have recently been identified as putative drivers in gliomas, acute myeloid leukemia (AML) and rare chondrosarcomas. In normal cells, Idh proteins are responsible for the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Neomorphic mutations in IDH1/2 were identified in the genomes of specific cancers that alter the enzymatic function of Idh to catalyze isocitrate into R(−)-2-hydroxyglutarate (2HG), an oncometabolite that inhibits α-KG-dependent dioxygenases activity, including Tet and JmjC, and leads to altered chromatin structures. IDH mutations are one of the earliest events detected in the both gliomas and leukemia, and are sufficient for promoting the hypermethylated state and driving tumorigenesis in these tumour types. Interestingly, despite their significant roles in brain and blood cell transformation, IDH mutations are rarely found in other tumour types, suggesting an as yet unknown relationship between these disparate tumours. Our objective is to understand why IDH mutations are only recurrent in gliomas, leukemia and chondrosarcomas and to identify the epigenetic consequences of IDH mutations in these tumour types.
Alireza Lorzadeh, Misha Bilenky, Colin Hammond, David J.H.F. Knapp, Luolan Li, Paul H. Miller, Annaick Carles, Alireza Heravi-Moussavi, Sitanshu Gakkhar, Michelle Moksa, Connie J. Eaves and Martin Hirst. Nucleosome Density ChIP-Seq Identifies Distinct Chromatin Modification Signatures Associated with MNase Accessibility. Cell Reports 17, 2112–2124, November 15, 2016
Gascard P, Bilenky M, Sigaroudinia M, Zhao J, Li L, Carles A, Delaney A, Tam A, Kamoh B, Cho S, Griffith M, Chu A, Robertson G, Cheung D, Li I, Heravi-Moussavi A, Moksa M, Mingay M, Hussainkhel A, Davis B, Nagarajan RP, Hong C, Echipare L, O’Geen H, Hangauer MJ, Cheng JB, Neel D, Hu D, McManus MT, Moore R, Mungall A, Ma Y, Plettner P, Ziv E, Wang T, Farnham PJ, Jones SJ, Marra MA, Tlsty TD, Costello JF, Hirst M. Epigenetic and transcriptional determinants of the human breast. Nat Commun. 2015 Feb 18
Li L., Lorzadeh A., Hirst M. Regulatory variation: an emerging vantage point for cancer biology. WIREs Syst Biol Med 2014, 6:37–59.
Li L., Memon S., Fan Y., Yang S., Tan S. Recent duplications drive rapid diversification of trypsin genes in 12 Drosophila. Genetica, 140 (7-9): 297-305.